GENETICA DI TUMORI INFANTILI E GIOVANILI Lucio Luzzatto, Scientific Director, Istituto Toscano Tumori, Firenze, ITALY MARCO VENTURINI in memoriam Negrar, 12 maggio 2012

MUTATION Normal tissue Tumor n-1 FORMATION OF A TUMOR RESULTS FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION

THE INCIDENCE OF CANCER DEPENDS STRONGLY ON AGE

THE MOST COMMON TYPES OF CANCER IN YOUNG PEOPLE Acute lymphatic leukemia (cALL) Medulloblastoma Glioma Neuroblastoma Wilms tumor Rhabdomyosarcoma Osteosarcoma Lymphoma Leukemia Testicular Melanoma Glioma Sarcomas Other Under 15 Age ____________________________

p53:SOMATIC MUTATIONS versus INHERITED MUTATIONS

BINDING TO CERTAIN SPECIFIC DNA ELEMENTS IS CRUCIAL TO THE FUNCTIONS OF p53

(From Monti et al., Clinical Cancer Research 13:3789,2007) I nherited mutants of p53 (Li-Fraumeni) with differentially altered transcriptional functionality cause different patterns of predisposition to cancer

WELLCOME TRUST SANGER INSTITUTE CANCER GENOME PROJECT NIH-NCI CANCER GENOME ANATOMY PROJECT Other major initiatives accessible on line:

(From Zhang et al., Nature, 2012) FEATURES OF HUMAN RETINOBLASTOMA ARE RERMARKABLY CONSERVED Original tumor Xenograft from above

From Zhang et al., Nature, 2012 GENOMIC PROFILE OF RETINOBLASTOMA IN TWO INDIVIDUAL PATIENTS

From Zhang et al., Nature, 2012 RETINOBLASTOMA HAS FEW MUTATIONS WHEN COMPARED TO OVARIAN CANCER

TYPES OF MUTATIONS IN HUMAN CANCER (From Futreal et al., 2004)

(From Shah et al, Nature 2012) DISTRIBUTION OF NUMBER OF SOMATIC MUTATIONS IN 65 CASES OF ‘TRIPLE NEGATIVE’ BREAST CANCER

* * * * MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA CORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES (From Kool et al., PLoS One 3:e3088,2008)

WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA ARE ANATOMICALLY DISTINCT (From Gibson et al., Nature 468:1095,2010)

(From Rausch et al., Cell 148:59,2012) CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS

144:9,2011

CHROMOTHRIPSIS Osteosarcoma (~25%) Then, confirmatory papers: Neuroblastoma 10 Medulloblastoma 4 Prostate 1 Multiple myeloma (~1.3%) Colon common Seminal paper by P J Stephens et al., Cell 144: 27–40 (January 7), Coined term and reported occurrence in several types of tumors, including:

(From Rausch et al., Cell 148:59,2012) DETAILED ANALYSIS OF CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS

(From Rausch et al., Cell 148:59,2012) Maximum amplicon count per chromosome Maximum number of copy number state changes per chromosome CORRELATION BETWEEN p53 STATUS AND CHROMOTRYPSIS IN MEDULLOBLASTOMA

(From Rausch et al., Cell 148:59,2012)

(From Demicco & Lazar, Seminars in Oncology 38:S3-S18,2011)

(From Demicco & Lazar, Seminars in Oncology 38:S3-S18,2011) Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2

(From Demicco & Lazar, Seminars in Oncology 38:S3-S18,2011) Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3

(From Demicco & Lazar, Seminars in Oncology 38:S3-S18,2011) Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4

(From Barretina et al., Nature Genetics 42:715,2010) POINT MUTATIONS AND COPY NUMBER CHANGES IN DIFFERENT TYPES OF SOFT TISSUE SARCOMA

(From Barretina et al., Nature Genetics 42:715,2010) Depending on which protein domain is affected, different mutations in the PIK3CA gene can produce markedly different clinical course of soft tissue sarcoma.

PROTEINS INVOLVED IN THE t(X;18) CHARACTERISTIC OF SYNOVIAL SARCOMA (From Haldar, Randall & Capecchi Clin Orthop Relat Res 466:2156,2008)

STRATEGY TO PRODUCE IN THE MOUSE A MODEL OF HUMAN SYNOVIAL SARCOMA (From Haldar, Randall & Capecchi Clin Orthop Relat Res 466:2156,2008)

(From Haldar, Randall & Capecchi Clin Orthop Relat Res 466:2156,2008) EXPRESSION OF THE SYT-SSX2 FUSION GENE IN MYOBLASTS PRODUCES TUMORS THAT MIMIC HUMAN SYNOVIAL SARCOMA

(From Saito et al., Cancer Research 66:6919,2006) A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESIS MEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA

(From Saito et al., Cancer Research 66:6919,2006) MODALITIES/EXTENT OF CADHERIN SYNTHESIS DEREPRESSION IN SYNOVIAL SARCOMA DEPEND ON THE SYT PARTNER IN SYT-SSX FUSIONS

MUTATION Normal tissue Tumor n-1 FORMATION OF A TUMOR RESULTS FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION Process can be accelerated by: - Increased rate of mutations - Increased number of cell divisions

CHANCE ENVIRONMENT INHERITANCE

ONCOGENE ADDICTION …The apparent dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype Bernard Weinstein Clin Cancer Res 3:2696,1997 Science 297:63,2002 Cancer Res 68:3077,2008

MODEL OF ONCOGENE ADDICTION (From Torti & Trusolino EMBO Mol Med 3:623,2011)

Anti-angiogenici Anti-infiammatori Immunomodulatori Interferenza con molecola iper-espressa in un tumore (p.es. trastuzumab) Farmaci che agiscono sul DNA e sulla mitosi (chemioterapici classici) Inibitori di un signal transduction pathway importante in un certo tumore (p.es. sunitinib) Interferenza con molecole mutate oncogeniche (p.es. imatinib, gefitinib)

TO UNDERSTAND, TO TREAT TO PREVENT CANCER AT BEST FOR ALL AOU Pisana AUSL 5 Pisa AUSL 6 Livorno - Ospedali Riuniti AUSL 9 Grosseto